Autoimmunity to ECGF in Lyme disease and its post-infectious syndromes

莱姆病及其感染后综合征中 ECGF 的自身免疫

• 批准号: 9067207
• 负责人: ALLEN C STEERE
• 金额: $ 43.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9067207
• 关键词: Accounting; Address; Antibiotic Therapy; Antibiotics; Antibody Response; Applications Grants; Arthritis; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Borrelia burgdorferi; Cells; Clinical; Complement; Complication; Cytokeratin; Disease; European; Facial paralysis; Fatigue; Fibroblast Growth Factor; Freezing; Grant; Health; Immune; Immune response; Infection; Inflammation; Integration Host Factors; Joints; Lead; Learning; Liquid substance; Location; Lyme Arthritis; Lyme Disease; Neuraxis; Neurocognitive; Order Spirochaetales; Pain; Pathogenesis; Patients; Physicians; Play; Proteomics; Publishing; Refractory; Research; Resolution; Role; Seminal; Serum; Symptoms; Syndrome; Synovitis; T-Lymphocyte; Testing; Tissue Sample; Tissues; To autoantigen; Translational Research; Work; adaptive immunity; base; candidate identification; innovation; killings; nervous system disorder; research clinical testing; response; translational approach

DESCRIPTION (provided by applicant): The greatest remaining clinical problem in Lyme disease (LD) is that some patients do not have complete resolution of signs or symptoms with antibiotic therapy. In recent years, we have studied this problem intensively in patients with Lyme arthritis in whom synovitis persists for months or years after spirochetal killing with antibiotics, called antibiotic-refractory arthritis. We have hypothesized that this disease course results from infection-induced autoimmunity with excessive inflammation and immune dysregulation in joints. However, until recently, identification of pathogenic autoantigens has remained elusive. Using discovery-based proteomics combined with clinical translational research, we recently identified endothelial cell growth factor (ECGF), the first known autoantigen that induces T and B cell responses in some patients with LD. In addition, we have preliminary information that the third component of complement and cytokeratin 10 may also serve as autoantigens. Our first specific aim in this grant application is to determine the clinica correlates of autoimmunity to ECGF or other candidate autoantigens across the spectrum of LD, including its post-infectious syndromes, to assess whether these responses are specific for LD, and to learn whether they occur only with U.S. B. burgdorferi (Bb) strains or also with European genospecies of the spirochete. Second, we plan to use the same proteomic and translational research approach that we employed successfully in the identification of ECGF to identify other candidate autoantigens. Third, we will determine spirochetal and host factors, including types of Bb strains and interactions with host cells, which are necessary for the induction of immune responses to ECGF of other candidate autoantigens, and we will characterize the adaptive immune response to these autoantigens in target tissues or fluids. These aims will allow us to determine whether autoimmunity to ECGF occurs as a part of a wider spectrum of Bb-induced immune responses, to ascertain the resulting clinical pictures, to identify other candidate autoantigens, and to delineate mechanisms responsible for these responses. We anticipate that a test for these antibody responses will become a part of the clinical evaluation of LD. Such information will help physicians to treat patients with LD more appropriately and effectively.

描述（由申请人提供）：莱姆病（LD）中最大的剩余临床问题是一些患者通过抗生素治疗无法完全解决体征或症状。近年来，我们对莱姆关节炎患者的这个问题进行了深入研究，这些患者在用抗生素杀死螺旋体后滑膜炎持续数月或数年，称为抗生素难治性关节炎。我们假设这种病程是由感染引起的自身免疫、关节过度炎症和免疫失调引起的。然而，直到最近，致病性自身抗原的鉴定仍然难以捉摸。利用基于发现的蛋白质组学与临床转化研究相结合，我们最近发现了内皮细胞生长因子 (ECGF)，这是第一个已知的可在某些 LD 患者中诱导 T 和 B 细胞反应的自身抗原。此外，我们初步了解到补体的第三种成分和细胞角蛋白10也可能作为自身抗原。我们在这项拨款申请中的第一个具体目标是确定自身免疫与 ECGF 或其他候选自身抗原在 LD 谱系（包括其感染后综合征）中的临床相关性，以评估这些反应是否对 LD 具有特异性，并了解它们是否仅发生在美国伯氏疏螺旋体 (Bb) 菌株中，或者也发生在欧洲螺旋体基因种中。其次，我们计划使用我们在 ECGF 鉴定中成功使用的相同蛋白质组学和转化研究方法来鉴定其他候选自身抗原。第三，我们将确定螺旋体和宿主因素，包括 Bb 菌株的类型以及与宿主细胞的相互作用，这些因素对于诱导对其他候选自身抗原的 ECGF 的免疫反应是必要的，并且我们将表征目标组织或体液中对这些自身抗原的适应性免疫反应。这些目标将使我们能够确定 ECGF 自身免疫是否作为更广泛的 Bb 诱导的免疫反应的一部分发生，以确定由此产生的临床表现，识别其他候选自身抗原，并描述导致这些反应的机制。我们预计这些抗体反应的测试将成为 LD 临床评估的一部分。这些信息将帮助医生更适当、更有效地治疗 LD 患者。